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A genetic approach to elucidate the genotoxic pathway of monomethylarsonousacid (MMAIII) suggests a key role for catalase
Citation:
Muniz Ortiz, J. G., K. WALLACE, AND A. D. KLIGERMAN. A genetic approach to elucidate the genotoxic pathway of monomethylarsonousacid (MMAIII) suggests a key role for catalase. Presented at Genetics Environmental Mutagenesis Society (GEMS) Fall Meeting, Chapel Hill, NC, November 08, 2011.
Impact/Purpose:
Our results suggest that catalase is involved in protecting cells against MMAIII~generated H202, and that •OH might be involved in its genotoxic pathway. Furthermore, individuals who harbor genetic polymorphisms in their catalase gene could exhibit enhanced susceptibility to arsenic toxicity.
Description:
Arsenic-contaminated drinking water causes cancer, neuropathy, respiratory effects, diabetes, and cardiovascular disease. Its exact mode of action (MOA) is not fully understood. Oxidative stress has been proposed as a key event in the toxic MOA of arsenic. Our studies are centered on identifying a reactive oxygen species involved in the genotoxicity of arsenic using a catalase (Cat) knockout mouse model, which is impaired in its ability to break down hydrogen peroxide (H202) leading to an increase in hydroxyl radicals (•OH). We assessed the induction of DNA damage using the comet assay following exposure of Cat+/+ and Cat–/–: primary mouse splenocytes to monomethylarsonous acid (MMAIII) to identify the potential role of H202 in arsenic's toxicity. Cat–/– splenocytes are more susceptible to MMAIII than the Cat+/+ splenocytes by a small (1.5-fold), but statistically significant margin. In mice splenocytes have one-third of the liver catalase activity. Therefore, comet assays were performed on MMAIIII-treated primary Cat+/+: , Cat+/–, and Cat–/– hepatocytes to determine if the Cat–/– cells were more susceptible to the treatment. Indeed Cat–/– hepatocytes exhibited higher levels of DNA strand breakage than the Cat+/+: and Cat+/–hepatocytes. Our results suggest that catalase is involved in protecting cells against MMAIII~generated H202, and that •OH might be involved in its genotoxic pathway. Furthermore, individuals who harbor genetic polymorphisms in their catalase gene could exhibit enhanced susceptibility to arsenic toxicity. [This is an abstract or proposed presentation and does not necessarily reflect EPA policy.]